The primary cause of AIDS (acquired immunodeficiency syndrome) in humans has been identified as the infection of cells of the immune system by the human immunodeficiency virus (HIV-1 or HIV-2) through sexual contact or the exchange of blood. Individuals infected with HIV vary in their rate of development of AIDS, suggesting that co-factors other than the virus itself are involved in influencing the rate of disease progression. Opioid addicts make up a significant portion of the AIDS population. The long-term objective of our research is to determine whether the cyclical effects induced by short-acting opioids on an individuals immune system will alter the process from initial viral exposure to the development of full-blown AIDS. Using the simian immunodeficiency virus (SIV) and rhesus monkeys (Macaca mulatta) as an animal model system for studying viral pathogenesis and AIDS, the objective of the current proposal is to continue our previous studies in evaluating the effects of morphine dependence on the viremia and on disease development after inoculation with SIVmac239, a molecular clone of SIV. Special reference will be made to mutations of the virus and sequential alterations in CD8+ functions. The specific aims are (l) to study the effects of oral methadone treatment versus the effects of morphine treatment on simian AIDS progression, (2) to compare the effects of morphine treatment versus the effects of morphine with the use of the antagonist naltrexone, and (3) to evaluate immunosuppressive treatment of the progression of the viremia using cyclosporin A with and without the administration of morphine. Methods of investigation include evaluation of the effects of SIV infection and opioid treatment on polymorphonuclear cell (PMN) chemotaxis and phagocytosis activities, neutralizing antibody titers, T-helper cell and natural killer cell functions, CD8+ antiviral activity, the occurrence of escape viral mutants, and SIV-induced programmed cell death. Recognizing the importance of opioids in AIDS pathogenesis and the use of effective drug abuse treatments such as methadone maintenance may result in the conception of new strategies of research and treatment for combatting the disease.